Peanut allergy is one of the most serious of the immediate hypersensitivity reactions to foods in terms of persistence and severity of reaction, and it appears to be a growing problem. A biased Th2/IgE immune reaction to peanut allergens is critical for the hypersensitivity response. The mechanisms leading to a lack of oral tolerance and generation of Th2/IgE bias to peanut allergens have remained undefined, hindering the development of new and effective approaches to prevent peanut as well as other food allergies. An understanding of the molecular mechanisms of peanut allergy is vital to ensure the eventual successful treatment of peanut allergic patients. Both genetic and environmental factors contribute to allergies. Environmental factors can be particularly important for food allergy because of the co-presence of commensal flora and food allergens in the gastrointestinal tract. The interplay between microbials and food allergens with the innate immune system may dictate the adaptive responses to allergens. Toll-like receptors (TLRs) are the major receptors for microbial recognition. TLR signals control adaptive immune responses by regulating antigen presentation and cytokine production by antigen presenting cells (APCs). In mice, deficiency of TLR4 can lead to hypersensitivity to peanuts. Furthermore, our preliminary data revealed that the cell signaling molecule diacylglycerol (DAG) kinase? (DGK?), which converts DAG to phosphatidic acid (PA) through phosphorylation, positively regulates TLR-induced IL-12 production. Deficiency of DGK? in mice causes significant hypersensitivity reactions to peanut allergens. We hypothesize that TLR-induced innate immune responses promote oral tolerance to peanut allergens and that inducing TLR-mediated innate immunity at the time of peanut allergen challenge may effectively decrease peanut allergenicity. Studies in this proposal are designed to establish a new murine model for peanut allergy, improve our understanding of the relationship between the innate and adaptive immune system in the development of oral tolerance, and develop a novel immunotherapy for treating peanut allergy patients. This grant application aims to investigate the mechanisms that are involved in the development of peanut allergy. The proposed studies are expected to determine the role of innate immune responses in the pathogenesis of peanut allergy by using a new murine model for the disease and also to provide new therapeutic reagents for peanut allergy by targeting the Toll-like receptors.